Chronic Lymphocytic Leukemia Drug Summary

Drug	Dosage	Remarks
Methylprednisolone	High dose with Rituximab: 1 g/m2 IV on days 1-5 of a 28-day cycle	Adverse Reactions CV effects (cardiomyopathy, hypertension, edema); CNS effects (headache, insomnia, psychiatric disturbances); GI effects (increased appetite, peptic ulcer, nausea, indigestion); Dermatologic effects (bruising, urticaria, skin test reaction suppression, impaired wound healing); Other effects (DM, hypokalemia, pituitary adrenal axis suppression, growth suppression, weakness, osteoporosis) Special Instructions Contraindicated in patients with systemic fungal infections, varicella and concomitant administration of live or attenuated vaccines Use with caution in patients with tuberculosis, heart failure, recent myocardial infarction, diabetes mellitus, GI disease (eg diverticulitis, peptic ulcer, ulcerative colitis), hepatic/renal impairment, myasthenia gravis, osteoporosis, history of seizure disorder, thyroid dysfunction

Drug	Dosage	Remarks
Bendamustine hydrochloride	Recommended dose: 100 mg/m2 IV over 30 minutes on days 1 and 2 of a 28-day cycle, up to 6 cycles Combination chemotherapy: 70-90 mg/m2 IV on days 1-2 Dose per chemotherapeutic regimen may vary; please refer to specific protocol	Adverse Reactions GI effects (nausea/vomiting, diarrhea, dry mouth, constipation, stomatitis); Respiratory effects (cough, pneumonia, pulmonary fibrosis); CNS effect (headache); Hematologic effects (febrile neutropenia, hypokalemia, myelodysplastic syndrome); CV effect (cardiac failure); Renal effect (renal failure); Other effects (pyrexia, asthenia, fatigue, malaise, weakness, mucosal inflammation, dehydration) Special Instructions Contraindicated in patients with CrCl <40 mL/min, moderate-severe hepatic impairment Use with caution in patients with mild-moderate renal impairment, mild hepatic dysfunction Monitor for signs of infection, infusion reactions, anaphylaxis, tumor lysis syndrome, skin reactions
Chlorambucil	150 mcg/kg/day PO until the total leukocyte count falls to 10,000 µL Resume treatment 4 weeks after at dose of 100 mcg/kg 24 hourly Combination chemotherapy: Dose per chemotherapeutic regimen may vary; please refer to specific protocol	Adverse Reactions Hematologic effects (leukopenia, neutropenia, acute secondary malignancies, bone marrow suppression, thrombocytopenia, pancytopenia, anemia); CNS effects (seizures in children with nephrotic syndrome, movement disorders, seizures, peripheral neuropathy); Respiratory effects (interstitial pneumonia, interstitial pulmonary fibrosis); Hepatic effects (hepatotoxicity, jaundice); GI effects (nausea/vomiting, oral ulceration, diarrhea); Other effects (rash, irreversible bone marrow failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug fever, sterile cystitis, allergic reactions) Special Instructions Should be taken on an empty stomach, at least 1 hour before or 3 hours after meals Contraindicated in patients with recent chemoradiotherapy Use with caution in patients with renal/hepatic impairment, seizure disorder, acute secondary malignancies, children with nephrotic syndrome Vaccination with live vaccines is not recommended Not to exceed >0.1 mg/kg body wt/day in patients with bone marrow lymphocytic infiltration
Cyclophosphamide	Combination chemotherapy: FCR: 250 mg/m2 IV over 10-30 minutes on days 1-3 Dose per chemotherapeutic regimen may vary; please refer to specific protocol	Adverse Reactions GI effects (nausea/vomiting, anorexia, mucositis); GU effects (acute hemorrhagic cystitis, urinary fibrosis, renal tubular necrosis); Dermatologic effects (alopecia, rash); Respiratory effects (rhinorrhea, nasal congestion); Other effects (fertility impairment, SIADH may occur with doses >50 mg/kg, leukopenia, headache) Special Instructions Contraindicated in patients with bladder hemorrhage, bone marrow aplasia, acute infection, drug-/radiation-induced urothelial toxicity, porphyria Use with caution in patients with hepatic/renal impairment
Fludarabine	Combination chemotherapy: 25 mg/m2 BSA IV via bolus injection or infusion over 30 minutes 24 hourly on days 1-3 May repeat every 28 days x 6 cycles Dose per chemotherapeutic regimen may vary; please refer to specific protocol	Adverse Reactions CNS effects (peripheral neuropathy, agitation, confusion, visual disturbances, coma, progressive encephalopathy); Respiratory effects (cough, dyspnea, pneumonia); GI effects (nausea/vomiting, diarrhea, stomatitis, mucositis); Hematologic effects (hemolytic anemia, thrombocytopenia, neutropenia); Other effects (fever, fatigue, chills, edema, tumor lysis syndrome, skin rashes, blindness) Potentially fatal: Myelosuppression, fatal autoimmune hemolytic anemia Special Instructions Contraindicated in patients with renal impairment (CrCl <30 mL/min), decompensated hemolytic anemia Use with caution in patients with renal/hepatic impairment Not to be given with live vaccines Monitor CBC and Hb concentration, signs of autoimmune hemolytic anemia, tumor lysis syndrome in patients with high tumor burden

Drug	Dosage	Remarks
Acalabrutinib	Monotherapy: 100 mg PO 12 hourly until disease progression or unacceptable toxicity Combination with Obinutuzumab: 100 mg PO 12 hourly starting at cycle 1 for total of 6 cycles (Obinutuzumab is started at cycle 2) Combination with Venetoclax: 100 mg PO 12 hourly on cycles 1-14 Start Venetoclax during cycle 3 on day 1 with 5-week ramp-up then 400 mg PO 24 hourly until cycle 14	Adverse Reactions GI effects (diarrhea, nausea/vomiting, constipation, abdominal pain); Hematologic effects (hemorrhage/hematoma, decreased absolute neutrophil count, Hb and platelets); Dermatologic effects (rash, bruising); CV effects (atrial fibrillation, atrial flutter); Other effect (epistaxis) Special Instructions Contraindicated in patients with severe hepatic impairment Avoid concomitant use of H2-receptor antagonists Use with caution in patients receiving antiplatelet or anticoagulant therapy, with serious infections Monitor CBC, for signs and symptoms of infection, atrial fibrillation and atrial flutter, bleeding, skin cancers
Alemtuzumab	Day 1: 3 mg IV infusion over 2 hours Day 2: 10 mg IV infusion over 2 hours Day 3: 30 mg IV infusion over 2 hours Max maintenance dose: 30 mg given 3x weekly on alternate days can then be used for up to 12 weeks	Adverse Reactions GI effects (nausea/vomiting, abdominal pain, GI hemorrhage, stomatitis, mucositis, abnormal hepatic function, constipation, dyspepsia, ulcerative stomatitis, flatulence); Hematologic effects (febrile neutropenia, leukopenia, thrombocytopenia, bronchitis, pharyngitis); Respiratory effects (dyspnea, pneumonia, bronchitis, pharyngitis); Dermatologic effects (urticaria, rash, injection site reaction); CNS effects (confusion, anxiety, somnolence, depression, insomnia, headache); Other effects (cardiac and vascular disorders, fever, chills, decreased weight, musculoskeletal pain, hyperhidrosis, fatigue, asthenia, infections) Special Instructions Contraindicated in patients with severe hypersensitivity to murine proteins, active systemic infections, HIV infection and active secondary malignancies Avoid vaccination with live viral vaccines within 12 months following therapy Use with caution in patients with ischemic heart disease, angina and/or in patients on antihypertensive medication Perform regular and complete blood counts and platelet counts and increase frequency in patients who develop cytopenia
Duvelisib	Relapsed/refractory CLL after ≥2 prior therapies: 25 mg PO 12 hourly	Adverse Reactions GI effects (diarrhea, colitis, nausea); Hematologic effects (anemia, neutropenia); Respiratory effects (cough, upper respiratory tract infection [URTI]), pneumonia); Other effects (rash, fatigue, pyrexia, musculoskeletal pain, sepsis) Special Instructions Use with caution in patients with serious infections, diarrhea or colitis, elevated ALT/AST, cutaneous reactions Provide prophylaxis for Pneumocystis jirovecii and CMV Use with caution in patients with infections, non-infectious diarrhea or colitis, cutaneous reactions, non-infectious pneumonitis, elevated AST/ALT, thrombocytopenia, neutropenia Monitor blood counts, hepatic function, signs and symptoms of infection, development of severe diarrhea and colitis
Ibrutinib	Monotherapy or in combination with anti-CD20 mAb: 420 mg PO 24 hourly In combination with Venetoclax: Administered as a single agent for 3 cycles, followed by 12 cycles with Venetoclax Cycled every 28 days	Adverse Reactions Resp effects (pneumonia, URTI, sinusitis); Musculoskeletal effects (arthralgia, muscle spasms, pain); Hematologic effects (neutropenia, leukocytosis, thrombocytopenia, anemia, lymphocytosis, bruising, petechiae); GI effects (nausea/vomiting, diarrhea, constipation, dry mouth, stomatitis); Other effects (skin infections, headache, rash, atrial fibrillation, UTI, epistaxis, subdural hematoma, pyrexia, peripheral edema) Special Instructions Should not be taken with grapefruit juice Concomitant use of St John’s wort-containing preparations are contraindicated Use with caution in patients with bleeding-related events, severe hepatic/renal impairment, concomitantly using Warfarin, other vitamin K antagonists or other anticoagulant and antiplatelet therapy Monitor for fever, neutropenia and infections, atrial fibrillation; monitor CBC monthly
Idelalisib	With Rituximab: 150 mg PO 12 hourly	Adverse Reactions Hematologic effects (neutropenia, lymphopenia, thrombocytopenia, anemia, transient lymphocytosis); Respiratory effect (pneumonitis); GI effects (diarrhea, colitis, intestinal perforation, increased LFTs); Dermatologic effects (rashes, severe cutaneous reaction) Special Instructions Contraindicated in patients with history of serious allergic reactions including toxic epidermal necrolysis Use with caution in patients with severe hepatic impairment, chronic active hepatitis including viral hepatitis, increased pneumococcal sepsis risk, dehydration, children <18 years old Monitor ALT, AST, bilirubin every 2 weeks for the first 3 months, weekly if ≥ grade 2 elevation until resolved to grade ≤1 Monitor for signs and symptoms of infections Perform HBV, HCV screening prior to therapy
Lisocabtagene maraleucel	90-110 × 106 CAR-positive viable T cells IV	Adverse Reactions GI effects (nausea/vomiting, constipation, diarrhea, abdominal pain); Respiratory effect (cough); CNS effects (headache, dizziness, encephalopathy); CV effects (hypotension, tachycardia); Other effects (fatigue, cytokine release syndrome, musculoskeletal pain, infections - pathogen unspecified, decreased appetite, edema) Special Instructions For autologous use only Watch out for emergence of possible infections and hypogammaglobulinemia Monitor CBC
Obinutuzumab	Combination regimen: Cycle 1: 1,000 mg IV on days 1 and 2 (day 1: 100 mg; day 2: 900 mg), and on days 8 and 15 If the 1st bag is completed without IV rate modifications or interruptions, second bag may be administered on the same day. If with IV rate modifications or interruptions during the 1st 100 mg, second bag must be administered the next day Cycles 2 to 6: 1,000 mg administered on day 1 Duration of treatment: 28 days/cycle x 6 cycles	Adverse Reactions Respiratory effects (nasopharyngitis, rhinitis, cough, pharyngitis, URTI, sinusitis, pneumonia); GI effects (diarrhea, constipation, oral herpes, dyspepsia, colitis, hemorrhoids); Dermatologic effects (squamous cell carcinoma of the skin, alopecia, pruritus); Hematologic effects (neutropenia, decreased WBC and neutrophil count, leukopenia, thrombocytopenia, anemia); Musculoskeletal effects (back pain, arthralgia, chest pain, bone pain); Other effects (headache, insomnia, asthenia, depression, anxiety, atrial fibrillation, cardiac failure, hypertension, dysuria, urinary incontinence, UTI, weight gain, infusion-related reactions) Special Instructions Use with caution in patients with high tumor burden, renal impairment, cumulative illness rating scale >6 and CrCL <70 mL/min, acute life-threatening resp symptoms, infusion-related reactions, cardiac/pulmonary/neurologic diseases, increased risk for hypertensive crisis, tumor lysis syndrome, active/recurring/chronic infection Withhold vaccination with live virus vaccines during treatment and until B-cell recovery
Pirtobrutinib	200 mg PO 24 hourly until disease progression or unacceptable toxicity	Adverse Reactions Hematologic effects (neutropenia, anemia, thrombocytopenia); Respiratory effects (pneumonia, sepsis, febrile neutropenia); GI effect (GI hemorrhage); Other effects (fatal hemorrhage, palpitations, dizziness) Special Instructions Swallow tablets whole with water; do not cut, crush or chew Consider prophylaxis (eg vaccinations or antimicrobials) in patients who are at increased risk for infections Discontinue for 3-7 days pre- and post-surgery depending on the type of surgery and risk of bleeding Monitor CBC and renal function regularly during treatment
Rituximab	Combination chemotherapy: 375 mg/m2 IV on day 0 of first cycle followed by 500 mg/m2 IV on day 1 of each subsequent cycle or 375 mg/m2 BSA IV on day 0 of first cycle followed by a fixed dose of 1,600 mg SC/cycle on day 1 of each subsequent cycle for a total of 6 cycles Dose per chemotherapeutic regimen may vary; please refer to specific protocol	Adverse Reactions Hematologic effects (neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, angioedema); GI effect (nausea); Dermatologic effects (rash, alopecia, pruritus, urticaria); Respiratory effects (bronchitis, URTI); Other effects (chills, fever, headache, asthenia, infections, decreased IgG levels, infusion-related reactions) Special Instructions Contraindicated in patients with severe hepatic impairment, active infections, severe immunocompromised state, severe uncontrolled cardiac disease, severe heart failure Use with caution in patients with high tumor burden/high number of circulating malignant cells (>25 x 109/L), history of pulmonary insufficiency, pulmonary tumor, pulmonary tumor infiltration or other severe infusion-related symptoms, cardiac disease, severe active infections, HBV infection, history of recurring or chronic infections, PML Vaccination with live vaccines is not recommended Monitor blood counts including neutrophil and platelet counts regularly during therapy
Venetoclax	Dose titration Week 1: 20 mg PO 24 hourly Week 2: 50 mg PO 24 hourly Week 3: 100 mg PO 24 hourly Week 4: 200 mg PO 24 hourly Week ≥5: 400 mg PO 24 hourly Continue until disease progression or unacceptable toxicity Monotherapy: 400 mg PO 24 hourly after completing 5-week dose titration schedule Combination with Obinutuzumab: Cycle 1: Obinutuzumab on day 1, 2, and 15 then subsequent 5-week dose titration on day 22 for cycle 1 Cycle 2: Obinutuzumab on day 1 then subsequent 5-week dose titration on day 28 Cycles 3-12: 400 mg PO24 hourly on days 1-28 Cycled every 28 days x 12 cycles Combination with Acalabrutinib Cycle 1: 100 mg PO 12 hourly on day 1 Cycle 3: 400 mg PO 24 hourly on day 1 Continue until disease progression, unacceptable toxicity or completion of 14 treatment cycles Cycled every 28 days x 12 cycles or Acalabrutinib - Cycle 1-14: 100 mg PO 12 hourly Venetoclax - Cycle 3-14: Standard 5-week ramp-up on day 1, then 400 mg PO 24 hourly x 12 cycles Fixed duration, 14 x 28-day cycles Combination with Ibrutinib Continue 5-week ramp-up schedule on day 1 of cycle 4 then continue with 400 mg/day until the end of cycle 15 Combination with Rituximab Continue for 24 months from day 1 of cycle 1 of Rituximab	Adverse Reactions Hematologic effects (neutropenia, anemia, thrombocytopenia); GI effects (nausea, diarrhea); Other effects (URTI, fatigue, edema) Special Instructions Should be taken with food Ensure adequate hydration during therapy Monitor for signs of tumor lysis syndrome and neutropenia Vaccination with live attenuated virus vaccines is not recommended prior to, during, and after treatment
Zanubrutinib	160 mg PO 12 hourly or 320 mg PO 24 hourly	Adverse Reactions Hematologic effects (decreased neutrophil count, platelet count, WBC count, Hgb); Other effects (URTI, rash, bruising, diarrhea, cough) Special Instructions Use with caution in patients with severe hepatic impairment Monitor for bleeding, signs and symptoms of infection, atrial fibrillation and atrial flutter Monitor CBC during treatment

Drug	Dosage	Remarks
Human immunoglobulin (Human Ig, Human normal immunoglobulin, Intravenous immunoglobulin, IVIg)	CLL with severe secondary hypogammaglobulinemia and recurrent infections: 0.2-0.4 g/kg IV infusion every 3-4 weeks	Adverse Reactions CNS effects (fever, chills, dizziness, anxiety); CV effects (chest pain, hypotension, flushing, pallor, pulmonary embolism, thromboembolism, tachycardia); Dermatologic effects (eczema, urticaria); GI effects (nausea/vomiting, abdominal pain); Hematologic effects (hemolytic anemia, transient neutropenia); Other effects (acute renal failure, conjunctivitis, aseptic meningitis syndrome) Special Instructions Contraindicated in patients with hypersensitivity to immune globulin and blood products, with IgA deficiency Use with caution in patients with renal disease, DM, volume depletion, sepsis, paraproteinuria, with history of CV disease or thrombotic episodes

All dosage recommendations are for non-pregnant and non-breastfeeding women and non-elderly adults with normal renal and hepatic function unless otherwise stated. 
Not all products are available or approved for above use in all countries. 
Products listed in the Drug Summary are based on indications stated in the locally approved product monographs. 
Please refer to local product monographs in Related MIMS Drugs for country-specific prescribing information.